Control of body mass is essential for mammalian survival. Disorders of body mass regulation (e.g, obesity) are common, and have serious medical consequences, including insulin resistance/Type 2 diabetes and dyslipidemia/cardiovascular disease. Organisms regulate body mass by controlling food intake and energy expenditure. Regulation of these processes is complex, involving multiple mediators acting at several sites in the brain and peripheral tissues. The adipocyte hormone leptin plays an especially important role. Leptin acts on CMS leptin receptors (LR) to inhibit food intake and promote energy expenditure. LRs are found in the arcuate nucleus (ARC) of the hypothalamus, which has been viewed as the major site of leptin action, and in several other regions of the brain. Recent cell-specific knockout studies confirm the importance of ARC neurons, but indicate that sites elsewhere in the brain also are essential for leptin action. Most obese humans are resistant to leptin. Defining normal LR signaling mechanisms and how, and in which neurons, these pathways are perturbed in leptin resistance may suggest new anti-obesity therapies. The LR activates tyrosine kinase, Jak2, promoting downstream signals. We identified that protein-tyrosine phosphatase, PTP1B, is a key negative regulator of leptin signaling and body mass control. PTP1B acts by dephosphorylating Jak2, thereby terminating LR signaling. By generating and studying whole body and neuronal-specific PTP1 B-/-mice, we also found that PTP1B in neurons is essential for the development of leptin resistance. The overall goal of studies in this proposal is to elucidate the mechanisms bv which PTP1B regulates adiposity. Specific Aims are: 1) To determine the cellular and molecular basis for reduced body mass in neuronal PTP1 B-/- mice;2) To determine the role of PTP1B in specific subpopulations of hypothalamic neurons in regulating adiposity, using mouse lines that express Cre recombinase only in specific subtypes of neurons;3) Using genetic and biochemical approaches, to determine how PTP1B interacts with Socs3, another negative regulator of leptin action, as well as PTP1 B's close relative, T cell- Protein Tyrosine Phosphatase, to regulate leptin signaling. These studies will advance our understanding of the mechanisms for resistance to leptin action. The results will have important implications for understanding normal body mass control and its dysregulation in obesity.